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Literature summary for 3.4.11.6 extracted from

  • Lu, W.; Yao, X.; Ouyang, P.; Dong, N.; Wu, D.; Jiang, X.; Wu, Z.; Zhang, C.; Xu, Z.; Tang, Y.; Zou, S.; Liu, M.; Li, J.; Zeng, M.; Lin, P.; Cheng, F.; Huang, J.
    Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis (2017), J. Med. Chem., 60, 1817-1828 .
    View publication on PubMed

Application

Application Comment Organism
drug development Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis Homo sapiens

Crystallization (Commentary)

Crystallization (Comment) Organism
enzyme in complex with inhibitors SAHA or M344, X-ray diffraction structure determination and analysis Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
(S)-2-((2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido)-4-methylpentanoic acid
-
Homo sapiens
3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]-propanoic acid
-
Homo sapiens
4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide enzyme binding structure, overview Homo sapiens
abexinostat
-
Homo sapiens
belinostat
-
Homo sapiens
CUDC-101
-
Homo sapiens
entinostat
-
Homo sapiens
givinostat
-
Homo sapiens
JNJ-26481585
-
Homo sapiens
mocetinostat
-
Homo sapiens
additional information drug repurposing of histone deacetylase (HDAC) inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis, overview. Analysis of potential inhibitors of LTA4H across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray crystallographic investigation. Detailed mechanisms of down-regulation of proinflammatory cytokines by SAHA or M344 are determined in vivo. Cotreatment of N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide and (S)-2-((2S,3R)-3-amino-2-hydroxy-4-phenylbutanamido)-4-methylpentanoic acid synergistically represses the migration of neutrophil and LTB4-induced neutrophil migration is not affected by these treatments. Molecular modeling of HDAC inhibitors against LTA4H hydrolase and aminopeptidase Homo sapiens
N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide
-
Homo sapiens
panobinostat
-
Homo sapiens
pracinostat
-
Homo sapiens
resminostat
-
Homo sapiens
rocilinostat
-
Homo sapiens
scriptaid
-
Homo sapiens
suberanilohydroxamic acid enzyme binding structure, overview Homo sapiens
trichostatin A
-
Homo sapiens
tubacin
-
Homo sapiens
Valproate
-
Homo sapiens

Metals/Ions

Metals/Ions Comment Organism Structure
Zn2+ zinc metalloenzyme, enzyme LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein Homo sapiens

Organism

Organism UniProt Comment Textmining
Homo sapiens P09960
-
-

Source Tissue

Source Tissue Comment Organism Textmining
neutrophil
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
additional information the aminopeptidase binding site shares a similar structure to LTA4H (EC 3.3.2.6) at its ligand binding sites Homo sapiens ?
-
?

Subunits

Subunits Comment Organism
More LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein Homo sapiens

Synonyms

Synonyms Comment Organism
Aminopeptidase
-
Homo sapiens
More see also EC 3.3.2.6 Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.0003
-
pH and temperature not specified in the publication Homo sapiens 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide
0.00167
-
pH and temperature not specified in the publication Homo sapiens suberanilohydroxamic acid
0.0044
-
pH and temperature not specified in the publication Homo sapiens scriptaid
0.01
-
above, pH and temperature not specified in the publication Homo sapiens trichostatin A
0.01
-
above, pH and temperature not specified in the publication Homo sapiens Valproate
0.01
-
above, pH and temperature not specified in the publication Homo sapiens tubacin
0.01
-
above, pH and temperature not specified in the publication Homo sapiens JNJ-26481585
0.01
-
above, pH and temperature not specified in the publication Homo sapiens belinostat
0.01
-
above, pH and temperature not specified in the publication Homo sapiens entinostat
0.01
-
above, pH and temperature not specified in the publication Homo sapiens panobinostat
0.01
-
above, pH and temperature not specified in the publication Homo sapiens mocetinostat
0.01
-
above, pH and temperature not specified in the publication Homo sapiens resminostat
0.01
-
above, pH and temperature not specified in the publication Homo sapiens abexinostat
0.01
-
above, pH and temperature not specified in the publication Homo sapiens CUDC-101
0.01
-
above, pH and temperature not specified in the publication Homo sapiens givinostat
0.01
-
above, pH and temperature not specified in the publication Homo sapiens N-(6-(2-aminophenylamino)-6-oxyhexyl)-4-methylbenzamide
0.01
-
above, pH and temperature not specified in the publication Homo sapiens pracinostat
0.01
-
above, pH and temperature not specified in the publication Homo sapiens rocilinostat

General Information

General Information Comment Organism
malfunction LTB4 levels are persistently elevated in bronchoalveolar lavage fluid (BALF) of lipopolysaccharide (LPS)-induced ALI, and the leukotriene levels in pulmonary edema fluid are significantly higher in ALI patients compared to control patients with hydrostatic pulmonary edema. In addition, LTB4 level is increased in lung homogenates, and BALF of patients with IPF and the level of LTB4 correlate with the extent of fibrosis in histological sections Homo sapiens
additional information LTA4H folds into three domains and creates a deep cleft harboring the catalytic Zn2+ site, forming the active site with an L-shaped hydrophobic pocket deep into the protein Homo sapiens
physiological function leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme that exhibits LTA4H and aminopeptidase activities, it is a key enzyme in the biosynthesis of leukotriene B4 (LTB4). LTA4H is well-known to regulate chemotactic activity of human neutrophils. LTB4 is secreted by neutrophils at inflammation sites in response to formyl peptides, playing an important role in neutrophil activation and migration to formyl peptides Homo sapiens